DETRUSITOL

Main information

  • Trade name:
  • DETRUSITOL Tablets 1 Milligram
  • Dosage:
  • 1 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DETRUSITOL Tablets 1 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/080/001A
  • Authorization date:
  • 05-10-2001
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Detrusitol1mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1mgtolterodinetartrateequivalentto0.68mgtolterodine.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Round,whitetabletswith‘TO’andarcsaboveandbelowtheletteringononesideandplainontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Symptomatictreatmentofurgeincontinenceand/orincreasedurinaryfrequencyandurgencyasmayoccurinpatients

withoveractivebladdersyndrome.

4.2Posologyandmethodofadministration

Adults(includingtheelderly):

Therecommendeddoseis2mgtwicedailyexceptinpatientswithimpairedliverfunctionorseverelyimpairedrenal

function(GFR ≤30ml/min)forwhomtherecommendeddoseis1mgtwicedaily(seesection4.4).Incaseof

troublesomeside-effectsthedosemaybereducedfrom2mgto1mgtwicedaily.

Theeffectoftreatmentshouldbere-evaluatedafter2-3months(seesection5.1).

PaediatricPatients:

EfficacyofDetrusitolhasnotbeendemonstratedinchildren(Seesection5.1).Therefore,Detrusitolisnot

recommendedforchildren.

4.3Contraindications

Tolterodineiscontra-indicatedinpatientswith:

urinaryretention,

uncontrollednarrowangleglaucoma,

myastheniagravis,

knownhypersensitivitytotolterodineorexcipients,

severeulcerativecolitis,

toxicmegacolon.

4.4Specialwarningsandprecautionsforuse

Tolterodineshouldbeusedwithcautioninpatientswith:

significantbladderoutletobstructionatriskofurinaryretention,

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renalimpairment(seesection4.2)

hepaticdisease(seesection4.2and5.2)

autonomicneuropathy

hiatushernia.

riskofdecreasedgastrointestinalmotility.

Multipleoraltotaldailydosesofimmediaterelease4mg(therapeutic)and8mg(supratherapeutic)tolterodinehave

beenshowntoprolongtheQTcinterval(seesection5.1).Theclinicalrelevanceofthesefindingsisunclearandwill

dependonindividualpatientriskfactorsandsusceptibilitiespresent.

TolterodineshouldbeusedwithcautioninpatientswithriskfactorsforQT-prolongationincluding:

CongenitalordocumentedacquiredQTprolongation

Electrolytedisturbancessuchashypokalaemia,hypomagnesaemiaandhypocalcaemia

Bradycardia

Relevantpre-existingcardiacdiseases(i.e.cardiomyopathy,myocardialischaemia,arrhythmia,congestiveheart

failure)

ConcomitantadministrationofdrugsknowntoprolongQT-intervalincludingClassIA(e.g.quinidine,procainamide)

andClassIII(e.g.amiodarone,sotalol)anti-arrhythmics.

ThisespeciallyholdstruewhentakingpotentCYP3A4inhibitors(seesection5.1).Concomitanttreatmentwithpotent

CYP3A4inhibitorsshouldbeavoided(seesection4.5,Interactions).

Aswithalltreatmentsforsymptomsofurgencyandurgeincontinence,organicreasonsforurgeandfrequencyshould

beconsideredbeforetreatment.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

ConcomitantsystemicmedicationwithpotentCYP3A4inhibitorssuchasmacrolideantibiotics(e.g.erythromycinand

clarithromycin),antifungalagents(e.g.ketoconazoleanditraconazole)andantiproteasesisnotrecommendeddueto

increasedserumconcentrationsoftolterodineinpoorCYP2D6metaboliserswith(subsequent)riskofoverdosage(see

section4.4).

Concomitantmedicationwithotherdrugsthatpossessantimuscarinicpropertiesmayresultinmorepronounced

therapeuticeffectandside-effects.Conversely,thetherapeuticeffectoftolterodinemaybereducedbyconcomitant

administrationofmuscariniccholinergicreceptoragonists.

Theeffectsofprokineticslikemetoclopramideandcisapridemaybedecreasedbytolterodine.

Concomitanttreatmentwithfluoxetine(apotentCYP2D6inhibitor)doesnotresultinaclinicallysignificant

interactionsincetolterodineanditsCYP2D6-dependentmetabolite,5-hydroxymethyltolterodineareequipotent.

Druginteractionstudieshaveshownnointeractionswithwarfarinorcombinedoralcontraceptives

(ethinylestradiol/levonorgestrel).

AclinicalstudyhasindicatedthattolterodineisnotametabolicinhibitorofCYP2D6,2C19,2C9,3A4or1A2.

Thereforeanincreaseofplasmalevelsofdrugsmetabolisedbytheseisoenzymesisnotexpectedwhendosedin

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4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseoftolterodineinpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Consequently,Detrusitolisnotrecommendedduringpregnancy.

Lactation

Nodataconcerningtheexcretionoftolterodineintohumanmilkareavailable.Tolterodineshouldbeavoidedduring

lactation.

4.7Effectsonabilitytodriveandusemachines

Sincethisdrugmaycauseaccommodationdisturbancesandinfluencereactiontime,theabilitytodriveanduse

machinesmaybenegativelyaffected.

4.8Undesirableeffects

Duetothepharmacologicaleffectoftolterodineitmaycausemildtomoderateantimuscariniceffectslikedrynessof

themouth,dyspepsiaanddryeyes.

ThetablebelowreflectsthedataobtainedwithDetrusitolinclinicaltrialsandfrompostmarketingexperience.The

mostcommonlyreportedadversereactionwasdrymouth,whichoccurredin35%ofpatientstreatedwithDetrusitol

tabletsandin10%ofplacebotreatedpatients.Headacheswerealsoreportedverycommonlyandoccurredin10.1%of

patientstreatedwithDetrusitoltabletsandin7.4%ofplacebotreatedpatients.

VeryCommon(

1/10) Common(

1/100and<1/10) Uncommon

(1/1000

and<1/100) Notknown

(cannotbe

estimatedfromthe

availabledata)

Infectionsand

infestations Bronchitis

Immunesystem

disorders Hypersensitivity

nototherwise

specified Anaphylactoid

reactions

Psychiatricdisorders Nervousness Confusion

hallucinations,

disorientation

Nervoussystem

disorders Headaches Dizziness,

somnolence,

paresthesia Memory

impairment

Eyedisorders Dryeyes,

abnormalvision

including

abnormal

accomodation

Earandlabyrinth

disorders Vertigo

Cardiacdisorders Palpitations Tachycardia,

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Casesofaggravationofsymptomsofdementia(e.g.confusion,disorientation,delusion)havebeenreportedafter

tolterodinetherapywasinitiatedinpatientstakingcholinesteraseinhibitorsforthetreatmentofdementia.

Paediatricpatients

IntwopaediatricphaseIIIrandomised,placebo-controlled,double-blindstudiesconductedover12weekswhereatotal

of710paediatricpatientswererecruited,theproportionofpatientswithurinarytractinfections,diarrhoeaand

abnormalbehaviourwashigherinpatientstreatedwithtolterodinethanplacebo(urinarytractinfection:tolterodine6.8

%,placebo3.6%;diarrhoea:tolterodine3.3%,placebo0.9%;abnormalbehaviour:tolterodine1.6%,placebo0.4%).

(Seesection5.1)

4.9Overdose

ThehighestdosegiventohumanvolunteersoftolterodineL-tartrateis12.8mgassingledose.Themostsevereadverse

eventsobservedwereaccommodationdisturbancesandmicturitiondifficulties.

Intheeventoftolterodineoverdose,treatwithgastriclavageandgiveactivatedcharcoal.

Treatsymptomsasfollows:

Severecentralanticholinergiceffects(e.g.hallucinations,severeexcitation):treatwithphysostigmine.

Convulsionsorpronouncedexcitation:treatwithbenzodiazepines.

Respiratoryinsufficiency:treatwithartificialrespiration.

Tachycardia:treatwithbeta-blockers.

Urinaryretention:treatedwithcatheterization.

Mydriasis:treatwithpilocarpineeyedropsand/orplacepatientindarkroom

AnincreaseinQTintervalwasobservedatatotaldailydoseof8mgimmediatereleasetolterodine(twicethe

recommendeddailydoseoftheimmediatereleaseformulationandequivalenttothreetimesthepeakexposureofthe

prolongedreleasecapsuleformulation)administeredoverfourdays.Intheeventoftolterodineoverdose,standard

supportivemeasuresformanagingQTprolongationshouldbeadopted.

5PHARMACOLOGICALPROPERTIES

arrhythmia

Vasculardisorders Flushing

Gastrointestinal

disorders Drymouth Dyspepsia,

constipation,

abdominalpain,

flatulence,

vomiting,

diarrhoea Gastroesophageal

reflux

Skinandsubcutaneous

tissuedisorders Dryskin Angioedema

Renalandurinary

disorders Dysuria,

urinaryretention

Generaldisordersand

administrationsite

conditions Fatigue,

headache,chest

pain,peripheral

oedema

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Pharmacotherapeuticgroup:Urinaryantispasmodics/

ATCcode:G04BD07

Tolterodineisacompetitive,specificmuscarinicreceptorantagonistwithaselectivityfortheurinarybladderover

salivaryglandsinvivo.Oneofthetolterodinemetabolites(5-hydroxymethylderivative)exhibitsapharmacological

profilesimilartothatoftheparentcompound.Inextensivemetabolisersthismetabolitecontributessignificantlytothe

therapeuticeffect(seeSection5.2).

Effectofthetreatmentcanbeexpectedwithin4weeks.

EffectoftreatmentwithDetrusitol2mgtwicedailyafter4and12weeks,respectively,comparedwithplacebo

(pooleddata).Absolutechangeandpercentagechangerelativetobaseline.

n.s.=notsignificant;*=p ≤0.05;**=p≤0.01;***=p≤0.001

Theeffectoftolterodinewasevaluatedinpatients,examinedwithurodynamicassessmentatbaselineand,depending

ontheurodynamicresult,theywereallocatedtoaurodynamicpositive(motorurgency)oraurodynamicnegative

(sensoryurgency)group.Withineachgroup,thepatientswererandomisedtoreceiveeithertolterodineorplacebo.The

studycouldnotprovideconvincingevidencethattolterodinehadeffectsoverplaceboinpatientswithsensoryurgency.

TheclinicaleffectsoftolterodineonQTintervalwerestudiedinECGsobtainedfromover600treatedpatients,

includingtheelderlyandpatientswithpre-existingcardiovasculardisease.ThechangesinQTintervalsdidnot

significantlydifferbetweenplaceboandtreatmentgroups.

TheeffectoftolterodineonQT-prolongationwasinvestigatedfurtherin48healthymaleandfemalevolunteersaged

18–55years.Subjectswereadministered2mgBIDand4mgBIDtolterodineastheimmediatereleaseformulations.

Theresults(Fridericiacorrected)atpeaktolterodineconcentration(1hour)showedmeanQTcintervalincreasesof5.0

and11.8msecfortolterodinedosesof2mgBIDand4mgBIDrespectivelyand19.8msecformoxifloxacin(400mg)

whichwasusedasanactive,internalcontrol.Apharmacokinetic/pharmacodynamicmodelestimatedthatQTcinterval

increasesinpoormetabolisers(devoidofCYP2D6)treatedwithtolterodine2mgBIDarecomparabletothose

observedinextensivemetabolisersreceiving4mgBID.

Atbothdosesoftolterodine,nosubject,irrespectiveoftheirmetabolicprofile,exceeded500msecforabsoluteQTcF

or60msecforchangefrombaselinethatareconsideredthresholdsofparticularconcern.The4mgBIDdose

correspondstoapeakexposure(C

)ofthreetimesthatobtainedwiththehighesttherapeuticdoseofDetrusitolSR

Variable 4-weekstudies 12-weekstudies

Detrusitol

2mgb.i.d. Placebo Statistical

significance

placebo Detrusitol

2mgb.i.d. Placebo Statistical

significance

placebo

Numberofmicturitions

per24hours -1.6

(-14%)

n=392 -0.9

(-8%)

n=189 * -2.3

(-20%)

n=354 -1.4

(-12%)

n=176 **

Numberofincontinence

episodesper24hours -1.3

(-38%)

n=288 -1.0

(-26%)

n=151 n.s. -1.6

(-47%)

n=299 -1.1

(-32%)

n=145 *

Meanvolumevoided

permicturition(ml) +25

(+17%)

n=385 +12

(+8%)

n=185 *** +35

(+22%)

n=354 +10

(+6%)

n=176 ***

Numberofpatientswith

noorminimalbladder

problemsaftertreatment

n=394 7%

n=190 ** 19%

n=356 15%

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Paediatricpatients

Efficacyinthepaediatricpopulationhasnotbeendemonstrated.Twopaediatricphase3randomised,placebo-

controlled,double-blind12weekstudieswereconductedusingtolterodineextendedreleasecapsules.Atotalof710

paediatricpatients(486ontolterodineand224onplacebo)aged5-10yearswithurinaryfrequencyandurgeurinary

incontinencewerestudied.Nosignificantdifferencebetweenthetwogroupswasobservedineitherstudywithregard

tochangefrombaselineintotalnumberofincontinenceepisodes/week.(Seesection4.8)

5.2Pharmacokineticproperties

Pharmacokineticcharacteristicsspecificforthisformulation:Tolterodineisrapidlyabsorbed.Bothtolterodineandthe

5-hydroxymethylmetabolitereachmaximalserumconcentrations1-3hoursafterdose.Thehalf-lifefortolterodine

givenasthetabletis2-3hoursinextensiveandabout10hoursinpoormetabolisers(devoidofCYP2D6).Steadystate

concentrationsarereachedwithin2daysafteradministrationofthetablets.

Fooddoesnotinfluencetheexposuretotheunboundtolterodineandtheactive5-hydroxymethylmetabolitein

extensivemetabolisers,althoughthetolterodinelevelsincreasewhentakenwithfood.Clinicallyrelevantchangesare

likewisenotexpectedinpoormetabolisers.

Absorption:AfteroraladministrationtolterodineissubjecttoCYP2D6catalysedfirst-passmetabolismintheliver,

resultingintheformationofthe5-hydroxymethylderivative,amajorpharmacologicallyequipotentmetabolite.

Theabsolutebioavailabilityoftolterodineis17%inextensivemetabolisers,themajorityofthepatients,and65%in

poormetabolisers(devoidofCYP2D6).

Distribution:Tolterodineandthe5-hydroxymethylmetabolitebindprimarilytoorosomucoid.Theunboundfractions

are3.7%and36%,respectively.Thevolumeofdistributionoftolterodineis113l.

Elimination:Tolterodineisextensivelymetabolisedbytheliverfollowingoraldosing.Theprimarymetabolicrouteis

mediatedbythepolymorphicenzymeCYP2D6andleadstotheformationofthe5-hydroxymethylmetabolite.Further

metabolismleadstoformationofthe5-carboxylicacidandN-dealkylated5-carboxylicacidmetabolites,whichaccount

for51%and29%ofthemetabolitesrecoveredintheurine,respectively.Asubset(about7%)ofthepopulationis

devoidofCYP2D6activity.Theidentifiedpathwayofmetabolismfortheseindividuals(poormetabolisers)is

dealkylationviaCYP3A4toN-dealkylatedtolterodine,whichdoesnotcontributetotheclinicaleffect.Theremainder

ofthepopulationisreferredtoasextensivemetabolisers.Thesystemicclearanceoftolterodineinextensive

metabolisersisabout30L/h.Inpoormetabolisersthereducedclearanceleadstosignificantlyhigherserum

concentrationsoftolterodine(about7-fold)andnegligibleconcentrationsofthe5-hydroxymethylmetaboliteare

observed.

The5-hydroxymethylmetaboliteispharmacologicallyactiveandequipotentwithtolterodine.Becauseofthe

differencesintheprotein-bindingcharacteristicsoftolterodineandthe5-hydroxymethylmetabolite,theexposure

(AUC)ofunboundtolterodineinpoormetabolisersissimilartothecombinedexposureofunboundtolterodineandthe

5-hydroxymethylmetaboliteinpatientswithCYP2D6activitygiventhesamedosageregimen.Thesafety,tolerability

andclinicalresponsearesimilarirrespectiveofphenotype.

Theexcretionofradioactivityafteradministrationof[ 14

C]-tolterodineisabout77%inurineand17%infaeces.Less

than1%ofthedoseisrecoveredasunchangeddrug,andabout4%asthe5-hydroxymethylmetabolite.The

carboxylatedmetaboliteandthecorrespondingdealkylatedmetaboliteaccountforabout51%and29%oftheurinary

recovery,respectively.

Thepharmacokineticsislinearinthetherapeuticdosagerange.

Specificpatientgroups:

Impairedliverfunction:About2-foldhigherexposureofunboundtolterodineandthe5-hydroxymethylmetaboliteis

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Impairedrenalfunction:Themeanexposureofunboundtolterodineandits5-hydroxymethylmetaboliteisdoubledin

patientswithsevererenalimpairment(inulinclearanceGFR ≤30ml/min).Theplasmalevelsofothermetaboliteswere

markedly(upto12-fold)increasedinthesepatients.Theclinicalrelevanceoftheincreasedexposureofthese

metabolitesisunknown.Thereisnodatainmildtomoderaterenalimpairment(seesection4.2and4.4).

Paediatricpatients

Theexposureoftheactivemoietypermgdoseissimilarinadultsandadolescents.Themeanexposureoftheactive

moietypermgdoseisapproximatelytwo-foldhigherinchildrenbetween5-10yearsthaninadults(Seesections4.2

and5.1).

5.3Preclinicalsafetydata

Intoxicity,genotoxicity,carcinogenicityandsafetypharmacologystudiesnoclinicallyrelevanteffectshavebeen

observed,exceptthoserelatedtothepharmacologicaleffectofthedrug.

Reproductionstudieshavebeenperformedinmiceandrabbits.

Inmice,therewasnoeffectoftolterodineonfertilityorreproductivefunction.Tolterodineproducedembryodeathand

malformationsatplasmaexposures(C

orAUC)20or7timeshigherthanthoseseenintreatedhumans.

Inrabbits,nomalformativeeffectwasseen,butthestudieswereconductedat20or3timeshigherplasmaexposure

orAUC)thanthoseexpectedintreatedhumans.

Tolterodine,aswellasitsactivehumanmetabolitesprolongactionpotentialduration(90%repolarisation)incanine

purkinjefibres(14–75timestherapeuticlevels)andblocktheK+-currentinclonedhumanether-a-go-go-relatedgene

(hERG)channels(0,5–26,1timestherapeuticlevels).IndogsprolongationoftheQTintervalhasbeenobservedafter

applicationoftolterodineanditshumanmetabolites(3,1–61,0timestherapeuticlevels).Theclinicalrelevanceof

thesefindingsisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Calciumhydrogenphosphatedihydrate

Sodiumstarchglycolate

Magnesiumstearate

Colloidalanhydroussilica

Hypromellose

Stearicacid

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Donotstoreabove25 °

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6.5Natureandcontentsofcontainer

Blisterpackscontaining28or56tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/80/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:05October2001

Dateoflastrenewal: 05October2006

10DATEOFREVISIONOFTHETEXT

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